High-Throughput Sequencing Shows Potentially Hundreds of Gene Mutations Related To Autism
News Jan 09, 2013
Genomic technology has revolutionized gene discovery and disease understanding in autism, according to an article published in the journal Neuron.
The paper highlights the impact of a genomic technology called high-throughput sequencing (HTS) in discovering numerous new genes that are associated with autism spectrum disorder (ASD).
"These new discoveries using HTS confirm that the genetic origins of autism are far more complex than previously believed," said Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center at the Icahn School of Medicine at Mount Sinai, and lead author of the article in Neuron.
Dr. Buxbaum is co-founder and co-director of the Autism Sequencing Consortium (ASC), a large multisite collaboration which is a model for future research. The co-authors of the article are Mark J. Daly, Broad Institute and Harvard Medical School; Bernie Devlin, University of Pittsburgh; Thomas Lehner, National Institute of Mental Health; Kathryn Roeder, Carnegie-Mellon University; Matthew W. State (co-director), Yale University, and the ASC.
HTS is a revolutionary new technology that allows scientists to obtain the sequence of all 22,000 human genes and the entire human genome in one experiment. This provides an unparalleled look at an individual’s genetic makeup and allows for gene discovery and for genetic testing.
"HTS shows us that there are not just a few mutations, but potentially hundreds of mutations that are linked to autism," said Dr. Buxbaum."By identifying the many genetic roots of this disorder, we can better understand its biology, which in turn will allow us to develop more tailored treatments for individuals.It is a transformative time for genetic research in autism."
Ground-breaking, highly reproducible discoveries identified through HTS described in the article include:
• the "staggering degree" of genetic heterogeneity in autism, which means that many individuals with autism do not share similar gene mutations;
• the identification of an increasing number of specific genes and chromosomal intervals conferring risk;
• the important emerging role in autism of both rare and "de novo germline mutations," or mutations developed in the sperm or ovaries of parents and passed on to children; and
• gene loci associated with autism that overlap with gene loci associated with other illnesses, such as intellectual disability and epilepsy.
Dr. Buxbaum estimates that researchers have already identified 50–100 specific genes and 20-40 chromosomal loci conferring risk. The researchers predict, based on the first studies in 1,000 families, that there are many hundreds of undiscovered ASD associated genes. This surge in the number of genes related to autism revealed by HTS marks a coming of age for high-throughput sequencing, the authors believe. The path forward for new discoveries, they write, is via one of two HTS processes: whole exome sequencing (WES) or whole genome sequencing (WGS) in large cohorts. The exome is the small fraction of the genome that codes for proteins.
The article spotlights the successful work of the ASC, founded in 2010, as a model to bring to fruition an explosive gene discovery process.The ASC member sites, using WES technology also available at Mount Sinai, recently discovered six de novo mutations in autism patients: CHD8, DYRK1A, GRIN2B, KATNAL2, POGZ and SCN2A.These six genes may be targets for future treatments. Some of these discoveries were accomplished rapidly because the Consortium’s 25 research groups, located around the world, combined their data and shared it before publication. As a result, they conducted four large studies using 1,000 families.
There are approximately 8,000 to 10,000 families currently available to the Consortium to study autism, but the article suggests many more are needed to speed up gene discoveries. Also needed for the future is increased collaboration among research teams and the integration of autism studies with studies of other psychiatric disorders. In addition, high-capacity supercomputers are needed to analyze the data. The ASC was designed to address these issues, and Mount Sinai has created Minerva, one of the largest academic supercomputers in the world, to help with these goals.
The research conducted at Mount Sinai was supported by grants from the National Institutes of Health and the Seaver Foundation.
Mechanism Controlling Multiple Sclerosis Risk IdentifiedNews
Researchers at Karolinska Institutet have now discovered a new mechanism of a major risk gene for multiple sclerosis (MS) that triggers disease through so-called epigenetic regulation. They also found a protective genetic variant that reduces the risk for MS through the same mechanism.
Synthetic DNA Shuffling Enzyme Outpaces Natural CounterpartNews
A new synthetic enzyme, crafted from DNA rather than protein, flips lipid molecules within the cell membrane, triggering a signal pathway that could be harnessed to induce cell death in cancer cells. Researchers say their lipid-scrambling DNA enzyme is the first in its class to outperform naturally occurring enzymes – and does so by three orders of magnitudeREAD MORE
Antarctic Worm and Machine Learning Help Identify Cerebral Palsy EarlierNews
A research team has released a study in the peer-reviewed journal BMC Bioinformatics showing that DNA methylation patterns in circulating blood cells can be used to help identify spastic cerebral palsy (CP) patients. The technique which makes use of machine learning, data science and even analysis of Antarctic worms, raises hopes for earlier targeted CP therapies.